This invention relates to certain novel octahydro-3-alkoxy-9-alkyl-phenanthridines and derivatives thereof and pharmaceutically acceptable acid addition salts thereof useful as antiinflammatory, analgesics, immunosuppressive, antiemetic and intraocular pressure reducing agents for use in mammals, including man; methods for their use and pharmaceutical compositions containing them.
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesics such as d-propoxyphene, codeine, and morphine, possess addictive liability. The need for improved and potent analgesics is, therefore, evident.
The major active ingredient of marijuana, .DELTA..sup.9 -terahydrocannabinol (.DELTA..sup.9 -THC), has been known to exert a wide range of pharmacological effects including analgesia, antiemetic, antiinflammation, immunosuppression, anticonvulsion and reduction of intraocular pressure in glaucoma (Dewley, W. L. Pharmac. Rev. 38, 151-178 (1986)). The clinical application of cannabinoids has, however, beeen limited by their pschoactive effects. In 1988, Devane et al (Mol. Pharmacol. 1988, 34, 605-613) reported the identification of a cannabinoid receptor in the brain (CB 1) which may be involved in cannabinoid-induced alterations in mood and cognition effect experienced by users of Marijuana. Recently a peripheral receptor for cannabinoids (CB2), that is not expressed in the brain but rather in macrophages in the marginal zone of spleen, has been isolated and characterized (Munro et al., Nature, 365, 61-65 (1993)). Thus a selective CB2 agonist can have antiinflammatory, analgesic, antiemetic, immunosuppressive and intraocular pressure reducing properties associated with cannabinoids without the pschoactive effects associated with CB 1 receptors.
It has been shown that certain 1,9-dihydroxy-octahydrobenzo-[c]quinolines (U.S. Pat. Nos. 4,260,764; 4,228,169) as well as the 9-oxo analogs (Belgian Pat. No. 854,655, 1977) are useful as CNS agents especially as analgesics and tranquilizers, as hypotensives, diuretics and as agents for treatment of glaucoma. The corresponding 9-amino and 9-oximino analogs have also been shown to have similar properties (U.S. Pat. No. 4,309,545).
Hoops et al., J. Org. Chem., 33, 2995-2996 (1968) describe the preparation of the 5-aza analog of delta-6a(10a)tetrahydrocannabinol referred to therein as 7,8,9,10-tetrahydro-1-hydroxy-5,6, 6,9-tetramethyl-3-n-pentylphenanthridine, but report no utility for the compound. Beil, in "Psychomimetic Drugs", edited by Efron, Raven Press, New York, 1970, page 336, reports the compound was "completely inert in animal pharmacology."
Hardman et al., Proc. West. Pharmacol. Soc., 14, 14-20 (1971) reports some pharmacological activity for 7,8,9,10-tetrahydro-1-hydroxy -6,6,9-trimethyl-3-n-pentyl phenanthridine, a 5-aza-delta6a(10)a-tetrahydrocannabinol. Paton, in Annual Review of Pharmacology, 15, 192 ( 1975), presents generalizations on structureaction relationships among cannabinoids. The presence of the gem dimethyl group in the pyran ring is critical for cannabinoid activity and substitution of N for O in the pyran ring removes activity. It has now been found that certain octahydro-3-alkoxy-9-alkyl-phenanthridine and derivatives are selective CB2 receptor agonists and are therfore effective in mammals, including man, as antiinflammatory, immunosuppressive, analgesics agents and useful in the treatment of glaucoma; as agents for treatment and prevention of emesis and nausea, especially that induced by antineoplastic drugs.